活动的Selumetinib神经纤维瘤类型1-Related丛状纤维瘤。

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Dombi E,鲍德温,马库斯LJ,费舍尔MJ,维斯B,金正日,惠特科姆P,马丁,Aschbacher-Smith勒,Rizvi助教,吴J, Ershler R,种P, Therrien J, Glod J,贝拉斯科JB, Schorry E, Brofferio, Starosta AJ, Gillespie,柯南道尔,拉特纳N, Widemann BC

活动的Selumetinib神经纤维瘤类型1-Related丛状纤维瘤。

郑传经地中海J。2016年12月29日,375 (26):2550 - 2560。doi: 10.1056 / NEJMoa1605943。

PubMed ID
28029918 (在PubMed
]
文摘

背景:缺乏有效的医学疗法治疗神经纤维瘤类型1-related丛状的纤维瘤,它的特点是高架RAS-mitogen-activated蛋白激酶(MAPK)信号。方法:我们进行了第一阶段试验selumetinib (AZD6244或进行- 142886),口服的选择性抑制剂MAPK激酶(MEK) 1和2,在儿童神经纤维瘤病1型和不实用的丛状纤维瘤确定最大耐受剂量和血浆药物动力学进行评估。Selumetinib是管理每天两次20到30毫克的剂量每平方米决定果蝇体表面积的连续计量进度(在28天周期)。我们还测试了selumetinib使用小鼠模型的神经纤维瘤1-related型神经纤维瘤。对治疗的反应(即。从基线,增加或减少的体积丛状纤维瘤)监控通过使用体积磁共振成像分析测量丛状神经纤维瘤的大小的变化。结果:共有24个儿童(平均年龄10.9岁;范围,3.0到18.5)肿瘤体积的中位数为1205毫升(8744)范围内,29日收到selumetinib。患者能够接收selumetinib在长期的基础上;中等数量的周期是30岁(范围,6 - 56)。 The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of >/=20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of >/=20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed. CONCLUSIONS: Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803 .).

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药物
药物靶点
药物 目标 类 生物 药理作用 行动
Selumetinib 双特异性增殖蛋白激酶激酶1 蛋白质 人类
是的
抑制剂
 细节
Selumetinib 双特异性增殖蛋白激酶激酶2 蛋白质 人类
是的
抑制剂
 细节